Many long noncoding RNAs (lncRNAs) have been annotated, but their functions remain unknown. The authors found a novel lnc-APUE (lncRNA accelerating proliferation by upregulating E2F1) that is upregulated in different cancer types, including hepatocellular carcinoma (HCC), and high lnc-APUE level is associated with short recurrence-free survival (RFS) of HCC patients. Gain- and loss-of-function analyses showed that lnc-APUE accelerated G1/S transition and tumor cell growth in vitro and allows hepatoma xenografts to grow faster in vivo. Mechanistically, lnc-APUE binds to miR-20b and relieves its repression on E2F1 expression, resulting in increased E2F1 level and accelerated G1/S phase transition and cell proliferation. Consistently, lnc-APUE level is positively associated with the expression of E2F1 and its downstream target genes in HCC tissues. Further investigations disclose that hepatocyte nuclear factor 4 alpha (HNF4) binds to the lnc-APUE promoter, represses lnc-APUE transcription, then diminishes E2F1 expression and cell proliferation. HNF4 expression is reduced in HCC tissues and low HNF4 level is correlated with high lnc-APUE expression. Collectively, a HNF4/lnc-APUE/miR-20b/E2F1 axis in which HNF4 represses lnc-APUE expression and keeps E2F1 at a low level is identified. In tumor cells, HNF4 downregulation leads to lnc-APUE upregulation, which prevents the inhibition of miR-20b on E2F1 expression and thereby promotes cell cycle progression and tumor growth.